Due to gradual westernization of Korean dietary culture, related metabolic diseases are increasing. One of the representative metabolic diseases is diabetes. Diabetes causes high blood glucose which is due to accumulation of glucose in the blood, not being used as energy, because a glucose regulatory hormone, insulin, secreted from pancreatic beta cells is not produced in the required amount in the body or does not properly act on cells, and has a symptom of glucose being detected in urine. Generally, diabetes is classified into insulin-dependent diabetes (type 1 diabetes) and non-insulin-dependent diabetes (type 2 diabetes) depending on whether insulin is essential for treatment. Type 2 diabetes is non-insulin-dependent diabetes developed due to an insufficient insulin action because of insulin resistance, or a relatively lack of insulin, and 90% of the total patients with diabetes have type 2 diabetes, which is also called adult diabetes because it generally occurs in people in their thirties.
When diabetes is long-term, since glucose in the body is not normally absorbed, resulting in abnormal glucose, lipid and protein metabolisms, various diabetic side effects such as hyperinsulinemia, neurologic complications, diabetic retinopathy (non-proliferative retinopathy, proliferative retinopathy, diabetic cataract), renal failure, sexual dysfunction, a dermal disease (allergy), high blood pressure, arteriosclerosis, cerebrovascular apoplexy (stroke), a cardiac disease (myocardial infarction, angina pectoris, heart attack), and gangrene occur. Therefore, while studies on glucose transport and metabolic processes and insulin signal transduction systems have been actively conducted domestically or globally to understand various reasons and etiological causes of type 2 diabetes and establish improvement plans, a drug that can be fundamentally used as a cure has not yet been developed.
Currently known drugs for type 2 diabetes may be broadly divided into four types, sulfonylurea-based drugs inducing insulin secretion, biguanide-based drugs exhibiting an effect of transferring glucose to muscle cells and inhibiting glucose synthesis in the liver, an α-glucosidase inhibitor that inhibits an enzyme for generating glucose in the small intestine, and thiazolidinedione (TZD)-based drugs that activate PPAR-γ involved in differentiation of adipocytes. However, such oral blood glucose-lowering agents involve various side effects such as hypoglycemia (sulfonylurea-based drug), nephrotoxicity (biguanide-based drug), lactic acidosis (biguanide-based drug), and diarrhea and stomachaches (α-glucosidase inhibitor).
Meanwhile, a peroxisome is one of the intracellular organelles that cause such abnormal metabolic function, plays an important role in oxygen, glucose, lipid and hormone metabolisms, and even widely affects regulation of cell proliferation and differentiation, and regulation of inflammatory mediators. In addition, a peroxisome affects formation of the cell membrane and mast cells as well as insulin sensitivity due to lipid metabolism and glucose metabolism, and affects oxidative stress, thereby playing an important role in aging and tumorigenesis. A peroxisome proliferator-activated receptor (PPAR) is one of the nuclear receptors that regulate gene expression by ligand binding, and various fatty acids act as endogenous ligands. Currently known PPARs are PPAR-α, PPAR-β/δ, and PPAR-γ.
PPAR-γ is most commonly found in adipose tissue, in addition to vascular endothelium, macrophages, and pancreatic β cells, and plays a critical role in regulating the differentiation of adipocytes and in systemic lipid homeostasis. An overall or partially-activated PPAR-γ compound is particularly effective in treating type 2 diabetes. However, obesity, dyslipidemia, a cardiovascular disease or fatty liver, which occurs as a side effect in PPAR-γ activation, becomes a problem.
PPAR-α is generally found in blood vessel walls, liver, heart, muscle, kidney, and brown adipose tissue, etc., prevents or delays arteriosclerosis together with an agonist, a fibrate, and exhibits an anti-obesity effect due to stimulation of fat oxidation.
Accordingly, to prevent, alleviate or treat various diseases regulated by a PPAR action, there is an increasing need to find a new compound that can effectively regulate PPAR activity.
For this reason, during research on compounds that have excellent antidiabetic activity and are capable of being safely applied, the inventors noticed amodiaquine.
There have been a variety of reports on amodiaquine, which is an anti-malarial compound, from studies on therapeutic agents for malaria. In addition, conventional patent technologies for amodiaquine include an anti-malarial mixed preparation for oral administration and a method of preparing the same (Korean Patent No. 10-0623322), and a piperazine derivative as an anti-malarial preparation (Korean Patent No. 10-1423785).
However, there are almost no studies and technologies with respect to amodiaquine for preventing, alleviating or treating a metabolic disease as a disease regulated by a PPAR action.